[go: up one dir, main page]

US8088804B2 - N-hydroxyamide derivatives possessing antibacterial activity - Google Patents

N-hydroxyamide derivatives possessing antibacterial activity Download PDF

Info

Publication number
US8088804B2
US8088804B2 US12/097,307 US9730706A US8088804B2 US 8088804 B2 US8088804 B2 US 8088804B2 US 9730706 A US9730706 A US 9730706A US 8088804 B2 US8088804 B2 US 8088804B2
Authority
US
United States
Prior art keywords
following method
methyl
prepared
nmr
calcd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US12/097,307
Other languages
English (en)
Other versions
US20100022605A1 (en
Inventor
Rakesh Kumar Jain
Mikhail Fedorovich Gordeev
Jason Gustaf Lewis
Charles Francavilla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp SRL
Vicuron Holdings LLC
Original Assignee
Pfizer Corp SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Corp SRL filed Critical Pfizer Corp SRL
Priority to US12/097,307 priority Critical patent/US8088804B2/en
Assigned to VICURON PHARMAECUTICALS INC. reassignment VICURON PHARMAECUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GORDEEV, MIKHAIL FEDOROVICH, LEWIS, JASON GUSTAF, FRANCAVILLA, CHARLES, JAIN, RAKESH KUMAR
Assigned to VICURON HOLDINGS LLC reassignment VICURON HOLDINGS LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VICURON PHARMACEUTICALS INC.
Publication of US20100022605A1 publication Critical patent/US20100022605A1/en
Application granted granted Critical
Publication of US8088804B2 publication Critical patent/US8088804B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • N-hydroxyamide derivatives which inhibit UDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) and as a result, have gram negative antibacterial activity.
  • Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of Gram-negative bacteria. Lipid A is required for bacterial growth and inhibition of its biosynthesis is lethal to the bacteria. Furthermore, blocking Lipid A biosynthesis increases the sensitivity of bacteria to other antibiotics.
  • LPS lipopolysaccharide
  • LpxC catalyzes the removal of the N-acetyl group of UDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine.
  • the LpxC enzyme is essential in Gram negative bacteria for the biosynthesis of Lipid A, and it is notably absent from mammalian genomes. Since LpxC is essential for Lipid A biosynthesis and inhibition of Lipid A biosynthesis is lethal to bacteria, inhibitors of LpxC have utility as antibiotics. In addition, the absence of LpxC from mammalian genomes reduces potential toxicity of LpxC inhibitors in mammals. Accordingly, LpxC is an attractive target for antibacterial drug discovery.
  • R 1 is selected from the group consisting of H, N 3 , NH 2 , NHSO 2 CH 3 , NHCOH, NHCH 3 , F, OCH 3 , and OH;
  • R 2 is selected from the group consisting of H, OH, and NH 2 ;
  • R 3 is selected from the group consisting of H and CH 2 OCH 3 ;
  • R 4 is selected from the group consisting of CH 2 SCH 3 , CH 2 SO 2 CH 3 , SCH 3 , SO 2 CH 3 , and
  • W is selected from the group consisting of S, SO, and SO 2 ;
  • X 1 , X 2 , and X 3 are each independently selected from the group consisting of H and F, provided that at least one of X 1 , X 2 , and X 3 is F;
  • Y is a heteroaryl
  • n 0 or 1
  • n 1 or 2;
  • Ar is an optionally substituted aryl or heteroaryl
  • Forms of the compounds can include salts, such as pharmaceutically acceptable salts, solvates, hydrates or prodrugs of the described compounds.
  • the described compounds can also be part of a pharmaceutical composition, which can additionally include a pharmaceutically acceptable carrier, diluent or excipient.
  • Such compounds and compositions exhibit antibacterial activity and can be used accordingly.
  • N-hydroxyamide derivatives which inhibit LpxC and thereby possess Gram negative antibacterial activity.
  • a subset of the compounds of Formula I are the compounds of Formula I(a):
  • R 1 , R 2 and R 3 are not all H. In some additional embodiments, when R 1 is —OH, then at least one of R 2 and R 3 is not H.
  • R 1 may be H, N 3 , —NH 2 , —NHSO 2 CH 3 , NHCOH, NHCH 3 , F, —OCH 3 , or OH;
  • R 2 may be H, OH, or NH 2 ;
  • R 3 may be H or —CH 2 OCH 3 ;
  • Ar may be an optionally substituted aryl or heteroaryl.
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • R 1 is NH 2 , R 2 is H, and R 3 is H;
  • R 1 is H, R 2 is OH, and R 3 is CH 2 OCH 3 ;
  • R 1 is N 3 , R 2 is H, and R 3 is H;
  • R 1 is NHSO 2 CH 3 , R 2 is H, and R 3 is H;
  • R 1 is NHCOH, R 2 is H, and R 3 is H;
  • R 1 is NHCH 3 , R 2 is H, and R 3 is H;
  • R 1 is F, R 2 is H, and R 3 is H;
  • R 1 is OCH 3 , R 2 is H, and R 3 is H;
  • R 1 is OH, R 2 is OH, and R 3 is H;
  • R 1 is OH
  • R 2 is NH 2
  • R 3 is H.
  • R 1 when R 1 is OH, R 2 and R 3 are not both H and/or when R 2 is OH, both R 1 and R 3 are not H.
  • a subset of the compounds of Formula I(a) includes compounds of Formula I(a)(i):
  • R 1 may be N 3 , NH 2 , NHSO 2 CH 3 , NHCOH, NHCH 3 , F, or OCH 3 ; and wherein Ar is an optionally substituted aryl or heteroaryl.
  • R 1 may be N 3 , NH 2 , NHSO 2 CH 3 , NHCOH, NHCH 3 , F, or OCH 3 ; and wherein Ar is an optionally substituted aryl or heteroaryl.
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may include the following substituted aryl compound.
  • Some compounds having Formula I(a) include compounds 1-8 of Table 2.
  • Another subset of the compounds of Formula I(a) includes compounds of Formula I(a)(ii):
  • R 2 may be OH or NH 2 ; and wherein Ar may be an optionally substituted aryl or heteroaryl.
  • Compounds of this formula also include compounds with the following stereochemistry:
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • Specific compounds having Formula I(a)(ii) include compounds 9-12 of Table 2.
  • W may be S, SO, or SO 2 ; and Ar may be an optionally substituted aryl or heteroaryl.
  • W may be S, SO, or SO 2 ; and Ar may be an optionally substituted aryl or heteroaryl.
  • Ar may be an optionally substituted aryl or heteroaryl.
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compounds.
  • a subset of the compounds of Formula I(b) include compounds of Formula I(b)(i)
  • Ar includes any optionally substituted aryl, in one embodiment, Ar may also include the following substituted aryl compounds.
  • Particular embodiments of Formula I(b) include compounds 13-15, 18, 19 and 33 of Table 2
  • W may be S, SO or SO 2 ; and Ar may be an optionally substituted aryl or heteroaryl.
  • W may be S, SO or SO 2 ; and Ar may be an optionally substituted aryl or heteroaryl.
  • Ar may be an optionally substituted aryl or heteroaryl.
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • Particular embodiments of Formula I(c) include compounds 16 and 17 of Table 2.
  • W may be S, SO or SO 2 ; n is 1 or 2; and Ar may be an optionally substituted aryl or heteroaryl.
  • W may be S, SO or SO 2 ; n is 1 or 2; and Ar may be an optionally substituted aryl or heteroaryl.
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • W is S and n is 1;
  • W is S and n is 2;
  • W is SO 2 and n is 1;
  • W is SO 2 and n is 2.
  • Particular embodiments of Formula I(d) include compounds 26-29 of Table 2.
  • Y can be a heteroaryl; m is 0 or 1; and Ar can be an optionally substituted aryl or heteroaryl.
  • Y may be a 5-membered heteroaryl ring. Additionally, Y may be
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • Particular compounds of Formula I(e) include compounds 30 and 31 of Table 2.
  • R 4 may be —CH 2 SCH 3 , —CH 2 SO 2 CH 3 , —SCH 3 , —SO 2 CH 3 , or
  • Ar may be an optionally substituted aryl or heteroaryl.
  • These compounds also include: compounds with the following stereochemistry:
  • Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • Particular embodiments of Formula I(f) include compounds 26-31 of Table 2.
  • X 1 , X 2 , and X 3 may each independently be H or F; and Ar may be an optionally substituted aryl or heteroaryl. Although Ar includes any optionally substituted aryl or heteroaryl, in one embodiment, Ar may also include the following substituted aryl compound.
  • Ar groups may be one of the following:
  • Another subset of the compounds of Formula I include compounds of Formula I(g)(i):
  • Ar is an optionally substituted aryl or heteroaryl.
  • Ar groups include, but are not limited to,
  • Particular embodiments of Formula I(g) include compounds 21-25 of Table 2.
  • Another set of the compounds of include compounds of Formula II
  • Ar includes any optionally substituted aryl, in one embodiment, Ar may also include the following substituted aryl compound, such as in compound 32 of Table 2.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined herein.
  • the pharmaceutical compositions can further comprise one or more additional antibacterial agents, one of which may be active against Gram positive bacteria. One of which may also be active against Gram negative bacteria.
  • provided herein is a method for the treatment of a microbial infection in a mammal comprising administering to the mammal a therapeutically effective amount of a compound provided herein.
  • the compound can be administered to the mammal orally, parenterally, transdermally, topically, rectally, or intranasally in a pharmaceutical composition.
  • a method for the treatment of a microbial infection in a mammal comprising administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein.
  • the pharmaceutical composition may further one or more additional antibacterial agents, one of which may be active against Gram positive bacteria. One of which may also be active against Gram negative bacteria.
  • the pharmaceutical composition may be administered to the mammal orally, parenterally, transdermally, topically, rectally, or intranasally.
  • the infection is a Gram negative infection. In an additional embodiment, the infection may be a Gram positive infection.
  • N-hydroxyamide derivatives which inhibit LpxC and as a result, have gram negative antibacterial activity.
  • Other N-hydroxyamide derivatives that also inhibit LpxC were described in U.S. Application Ser. Nos. 60/394,862, filed Jul. 12, 2002, and 10/617,616, filed Jul. 11, 2003, the entirety of all of which are hereby expressly incorporated by reference in their entirety. However, the following terms will first be defined.
  • Halo means fluoro, chloro, bromo, or iodo.
  • Niro means the group —NO 2 .
  • Haldroxy means the group —OH.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms.
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like.
  • Alkylene means a linear divalent hydrocarbon group of one to eight carbon atoms or a branched divalent hydrocarbon group of three to eight carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, 2-methylpropylene, and the like.
  • Alkenyl means a linear unsaturated monovalent hydrocarbon radical of two to eight carbon atoms or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one double bond, (—C ⁇ C—). Examples of alkenyl groups include, but are not limited to, allyl, vinyl, 2-butenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to eight carbon atoms or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one triple bond, (—C ⁇ C—).
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, 2-butynyl, and the like.
  • Alkynylene means a linear divalent hydrocarbon radical of two to eight carbon atoms or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one triple bond, (—C ⁇ C—).
  • alkynylene groups include, but are not limited to, ethynylene, propynylene, and the like.
  • Alkylsilylalkynyl means the group (alkyl)3Si-alkynylene—where alkyl and alkynylene are as defined above.
  • Haloalkyl means an alkyl substituted with one or more, preferably one to 6, of the same or different halo atoms.
  • haloalkyl groups include, for example, trifluoromethyl, 3-fluoropropyl, 2,2-dichloroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl substituted with one or more —OH groups provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Examples of hydroxyalkyl groups include, for example, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and the like.
  • Alkylthio refers to the group “alkyl-S—” where alkyl is as defined above and which includes, by way of example, methylthio, butylthio, and the like.
  • Alkylsulfinyl refers to the group “alkyl-S(O)—” where alkyl is as defined above and which includes, by way of example, methyl-S(O)—, butyl-S(O)—, and the like.
  • Alkylsulfonyl refers to the group “alkyl-S(O) 2 —” where alkyl is as defined above and which includes, by way of example, methyl-S(O) 2 —, butyl-S(O) 2 —, and the like.
  • Alkoxy refers to the group “alkyl-O—”, wherein alkyl is as defined above, and which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkoxyalkyl refers to the group “-alkylene-O-alkyl” where alkylene and alkyl are as defined herein and which includes, by way of example, 2-propoxyethylene, 3-methoxybutylene, and the like.
  • Alkenoxy refers to the group “alkenyl-O—” where alkenyl is as defined herein and which includes, by way of example, allyloxy, vinyloxy, 2-butenyloxy, and the like.
  • alkenoxyalkyl refers to the group “alkenyl-O-alkylene” where alkenyl and alkylene are as defined herein and which includes, by way of example, 3-allyloxy-propylene, 2-(2-propenyloxy)ethylene, and the like.
  • Alkynyloxy refers to the group “alkynyl-O—” where alkynyl is as defined herein and which includes, by way of example, propargyloxy and the like.
  • Arylalkoxyalkyl refers to the group “aryl-alkoxy-alkylene-” where aryl, alkoxy and alkylene are as defined herein.
  • Haloalkoxy refers to the group “haloalkyl-O—” where haloalkyl is as defined herein and which includes, by way of example, trifluoromethoxy, 2,2-dichloroethoxy, and the like.
  • Haloalkylthio refers to the group “haloalkyl-S—” where haloalkyl is as defined herein which includes, by way of example, trifluoromethylthio, 2,2-difluoropropylthio, 3-chloropropylthio, and the like.
  • Haloalkyl-sulfinyl refers to the group “haloalkyl-S(O)—” where haloalkyl is as defined herein and which includes, by way of example, trifluoromethanesulfinyl, 2,2-dichloroethanesulfinyl, and the like.
  • Haloalkyl-sulfonyl refers to the group “haloalkyl-S(O) 2 —” where haloalkyl is as defined herein and which includes, by way of example, trifluoromethanesulfonyl, 2,2-dichloroethanesulfonyl, and the like.
  • Amino refers to the group “—NR a R b ” wherein R a and R b are independently H, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl where each of alkyl, haloalkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl are as defined herein.
  • Carbonyl means the group “—C(O)—.”
  • Carboxyl refers to —COOR where R is hydrogen, alkyl, aryl, heteroaryl and heterocycle or salts thereof.
  • Carboxylamide refers to —C(O)NR a R b ′′ wherein R a and R b are independently H, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl where each of alkyl, haloalkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl are as defined herein.
  • “Acyloxy” means the group —C(O)R′ wherein R′ is alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl where alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl are as defined herein.
  • Cycloalkyl means a cyclic saturated hydrocarbon group of 3 to 8 ring atoms, where one or two of C atoms are optionally replaced by a carbonyl group.
  • the cycloalkyl group may be optionally substituted with one, two, or three substituents, preferably alkyl, alkenyl, halo, hydroxyl, cyano, nitro, alkoxy, haloalkyl, alkenyl, and alkenoxy as these terms are defined herein.
  • Representative examples include, but are not limited to, cyclopropyl, cyclohexyl, cyclopentyl, and the like.
  • Cycloalkylalkyl means a group —R c R d where R c is an alkylene group and R d is a cycloalkyl group, as defined above. Examples include, but are not limited to, cyclopropylmethylene, cyclohexylethylene, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic carbocyclic group of 6 to 14 ring atoms. Examples include, but are not limited to, phenyl, naphthyl, and anthryl.
  • the aryl ring may be optionally fused to a 5-, 6-, or 7-membered monocyclic non-aromatic ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl.
  • fused ring systems are referred to herein as “cyclic moiety containing a total of 4, 5, 6, or 7 ring atoms.”
  • Representative aryl groups with fused rings include, but are not limited to, 2,5-dihydro-benzo[b]oxepine, 2,3-dihydrobenzo[1,4]dioxane, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole, 2,3-dihydro1H-isoindole, benzimidazole-2-one, 2-H-benzoxazol-2-one, and the like.
  • Substituted aryl means an aryl ring substituted with one or more substituents, preferably one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxyl, carboxy, cyano, nitro, and alkylthio as these terms are defined herein.
  • the aryl ring may be optionally fused to a 5-, 6-, or 7-membered monocyclic non-aromatic ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, or sulfur, the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C.
  • Representative examples include, but are not limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxa
  • Substituted heteroaryl means a heteroaryl ring substituted with one or more substituents, preferably one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxyl, carboxy, cyano, nitro, and alkylthio as these terms are defined herein.
  • Aryloxy means a group “—O—Ar” where Ar is an aryl group or substituted aryl group as these terms are defined herein. Examples include, but are not limited to, benzyloxy, 4-trifluoromethyl-benzyloxy, and the like.
  • Arylalkoxy means a group “—O-alkylene-Ar” where Ar is an aryl group or substituted aryl group as defined herein and alkylene is as also defined herein. Examples include, but are not limited to, 2-(phenyl)ethoxy, 3-(phenyl)propoxy, and the like.
  • Arylalkoxyalkyl means a group “-alkylene-O-alkylene-Ar” where Ar is an aryl group or substituted aryl group as defined herein and each alkylene is independently selected from the other, wherein alkylene is as also defined herein. Examples include, but are not limited to, benzyloxy-propylene, benzyloxy-ethylene, and the like.
  • Aminocarboxyalkyl means a group “—R c C(O)NR a R b ” where R c is an alkylene group as defined herein and R a and R b are as defined above.
  • Haloarylalkyl means the group “aryl-alkylene-” having 1 to 6 halo substituents on either the aryl and/or the alkylene groups where aryl and alkylene are as defined herein.
  • Haloarylalkenyl means the group “aryl-alkenylene-” having 1 to 6 halo substituents on either the aryl and/or the alkenylene groups where aryl and alkenylene are as defined herein.
  • Haloarylalkynyl means the group “aryl-alkynylene-” having 1 to 6 halo substituents on either the aryl and/or the alkynylene groups where aryl and alknyylene are as defined herein.
  • Heterocycle or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen within the ring, wherein, in fused ring systems one or more of the rings can be aryl or heteroaryl as defined herein.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydro-isoquinoline, 4,5,
  • Heterocycles may be optionally substituted with from one to three substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxyl, carboxy, cyano, nitro, and alkylthio as these terms are defined herein.
  • aryl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
  • a “pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier” as used in the specification and claims include both one and more than one such carrier.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • salt is refers to all salt forms of a compound, including salts suitable for use in industrial processes, such as the preparation of the compound, and pharmaceutically acceptable salts.
  • Treating” or “treatment” of a disease includes:
  • a “therapeutically effective amount” means the amount of a compound or mixture of compounds that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • Pro-drugs mean any compound which releases an active parent drug according to a compound provided herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound provided herein are prepared by modifying functional groups present in a compound provided herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs include compounds provided herein wherein a hydroxy, sulfhydryl or amino group in the compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to C 1 -C 10 esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-alkylaminocarbonyl) of hydroxy functional groups in compounds provided herein, and the like.
  • tautomers refers to herein as a constitutional isomer in which migration of a hydrogen atom results in two ore more structures.
  • the N-hydroxyamide may tautomerize to form a 1,2-dihydroxyimine.
  • mamal refers to all mammals including humans, livestock, and companion animals.
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Toranto Research Chemicals (North York, ON Canada), Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Matrix Scientific (Columbia, S.C., USA), Emka-Chemie, or Sigma (St.
  • protecting groups may prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular function groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • stereoisomers and enriched mixtures
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the conventional oxidation of the hydroxyl group of 12 provides N-protected 4-oxoproline methyl ester, 13 (Scheme 1).
  • Reaction of 13 with dibromomethane, Zn and bis(cyclopentadienyl)zirconium dichloride in organic solvent, for example, THF provided the alkene derivative 14.
  • Osmylation or catalytic asymmetric dihydroxylation in an organic solvent at 0° C. to 40° C. furnished the di-hydroxy 15.
  • the primary alcohol in 15 is selectively O-methylated with an alkylating agent in the presence of a base to provide the alkylated product 16 (Scheme 1).
  • Suitable methylating agents include trimethyloxonium tetrafluoroborate and the like.
  • the alkylation is conducted in an inert organic solvent such as, for example, N,N-dimethylformamide, acetonitrile, dichloromethane, and N-methylpyridone.
  • Suitable bases include, 2,6-di-tert-butyl-4-methylpyridine, triethylamine and the like.
  • the reaction is typically conducted at room temperature for about 2 to about 16 hours.
  • the methyl ester 16 is then treated with aqueous inorganic base in polar solvent to hydrolyze the methyl ester protecting group and then the carboxylic acid is coupled with an O-protected hydroxyl amine to provide amide 18.
  • a suitable base includes lithium hydroxide, sodium hydroxide and suitable organic solvents include methanol, tetrahydrofuran and dioxane.
  • the acid is coupled with the O-protected hydroxylamine using a coupling reagent such as HATU in an organic base in an inert organic solvent.
  • Suitable organic bases include DIEA, TEA, pyridine, and N-methyl morpholine
  • suitable inert organic solvents include N,N-dimethylformamide, acetonitrile, dichloromethane, and alike.
  • the O-protected amide 18 is then hydrogenated to remove the N-protecting group to provide an amine 19 (Scheme 1).
  • the hydrogenation is carried out in a polar organic solvent such as ethanol or methanol.
  • the reduction is carried out in the presence of a palladium catalyst under hydrogen atmosphere. The reduction may conveniently be carried out at ambient temperatures in about 2 minutes to 24 hours.
  • This reaction can be performed with any number of known coupling reagents, such as HATU, HOBT, carbodiimides, DPPA, and the like.
  • Suitable organic bases include DIEA, TEA, pyridine, N-methyl morpholine, and the like.
  • Suitable inert organic solvents which can be used include, for example, N,N-dimethylformamide, acetonitrile, dichloromethane, and the like. The reaction is continued until completion, which typically occurs in from about 2 to 12 hours.
  • the amide 20 is then converted to the N-hydroxyamide derivative of Formula I(a) by treatment with acid in a organic solvent such as dichloroethane, methylene chloride and the like.
  • a organic solvent such as dichloroethane, methylene chloride and the like.
  • the reaction is carried out at 0° C. to ambient temperature for about 1 to 6 hours.
  • the Boc-protected 21 is coupled with O-benzyl hydroxylamine under reactive conditions, preferably in an inert organic solvent, in the presence of a coupling reagent and an organic base to provide a benzyloxyamide 22 (Scheme 2).
  • This reaction can be performed with any number of known coupling reagents, such as HATU, HOBT, carbodiimides, DPPA, and the like.
  • Suitable organic bases include DIEA, TEA, pyridine, N-methyl morpholine, and the like.
  • Suitable inert organic solvents which can be used include, for example, N,N-dimethylformamide, acetonitrile, dichloromethane, and the like.
  • This reaction is typically conducted at temperatures in the range of about 0° C. to 25° C. The reaction is continued until completion, which typically occurs in from about 2 to 24 hours.
  • the hydroxylated 23 can be prepared by methods well known in the art (Scheme 2). Suitable hydroxylating agents for converting the alkene to the diol include OsO 4 and 4-methylmorpholine-N-oxide in t-butyl alcohol and Sharpless reagents. The reaction is generally carried out from about 12 to 24 hours.
  • the benzyloxyamide is then reacted with an acid to remove the t-butoxycarbonyl protecting group (Scheme 2).
  • Removal of the protecting group may be carried out with acids, such as a trifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid, and the like, in an inert organic solvent such as dichloromethane, dioxane, THF, and the like.
  • THF trifluoroacetic acid
  • the removal is typically conducted at low temperatures, e.g., 0° C., and then gradually allowed to warm to room temperature to provide the benzyloxyamide acid salt.
  • Amidation of the benzyloxyamide acid salt is then conducted with an optionally substituted biphenyl acid under reactive conditions, preferably in an inert organic solvent, in the presence of a coupling reagent and an organic base to provide an amide (25).
  • This reaction can be performed with any number of known coupling reagents, such as HATU, HOBT, carbodiimides, DPPA, and the like.
  • Suitable organic bases include DIEA, TEA, pyridine, N-methylmorpholine, and the like.
  • Suitable inert organic solvents which can be used include, for example, N,N-dimethylformamide, acetonitrile, dichloromethane, and the like.
  • This reaction is typically conducted using an excess of benzyloxyamide to benzoic acid at temperatures in the range of about 0° C. to about 50° C. The reaction is continued until completion, which typically occurs in from about 2 to 24 hours.
  • N-hydroxyamide derivative of Formula I(a) is then converted to the N-hydroxyamide derivative of Formula I(a) by hydrogenation to remove the benzyloxy protecting group (OBn (Scheme 2).
  • Oprotection is carried out in a polar organic solvent such as ethanol or methanol.
  • the hydrogenation is carried out at in the presence of a palladium (II) catalyst or palladium on carbon under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 1 to 24 hours.
  • the methyl ester of Boc-protected hydroxyproline carboxylic acid (3) can be generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • inversion of the 3-R-hydroxy substituent to the 3-S-hydroxy substituent in 3 can be accomplished by reaction with p-nitrobenzoic acid, phosphine and diisopropyl azodicarboxylate (DIAD) in a suitable solvent such as tetrahydrofuran, dioxane, and alike followed by deacylation with a suitable alkaline reagent such as LiOH in MeOH.
  • a suitable solvent such as tetrahydrofuran, dioxane, and alike
  • suitable alkaline reagent such as LiOH in MeOH.
  • the N-protected 3-hydroxyproline methyl ester, 3, can be used to prepare a variety of further derivatives.
  • reaction with fluorinated reagents e.g., dimethoxydimethylaminosulfurtrifluoride
  • deprotection provides for 3-fluoroproline methyl ester (4: R 1 ⁇ F).
  • alkylation of the hydroxyl group followed by nitrogen deprotection yields the 3-alkoxyproline methyl ester.
  • the substituted proline methyl ester 4 is then treated with an acid to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt 5.
  • Removal of the protecting group may be carried out with acids, such as a trifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid, and alike, in an inert organic solvent such as dichloromethane, dioxane, THF, and the like.
  • THF trifluoroacetic acid
  • the deprotection is typically conducted at low to ambient temperatures (e.g., 0° C.—r.t.).
  • the salt 5 is then condensed with an optionally substituted aromatic carboxylic acids under reactive conditions, preferably in an inert organic solvent, in presence of a coupling reagent and an organic base to provide an amide (6) (Scheme 3).
  • aromatic acids can be employed, e.g. biaryl carboxylic acid, or substituted biaryl carboxylic acid, etc.
  • This reaction can be performed with any number of known coupling reagents, such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT), carbodiimides, diphenylphosphoryl azide (DPPA), and alike.
  • Suitable organic bases include diisopropyethylamine (DIEA), TEA, pyridine, N-methyl morpholine, and alike.
  • Suitable inert organic solvents which can be used include, for example, N,N-dimethylformamide, acetonitrile, dichloromethane, and alike.
  • This reaction is typically carried out at temperatures in the range of about 0° C. to about 50° C. The reaction is continued until completion, which typically occurs in from about 2 to 24 hours.
  • methyl ester 6 can be directly converted into the hydroxamate 7 with a hydroxylamine reagent, such as aqueous (aq). hydroxylamine, or methanolic hydroxylamine HCl with NaOMe (see Scheme 4 below).
  • a hydroxylamine reagent such as aqueous (aq). hydroxylamine, or methanolic hydroxylamine HCl with NaOMe (see Scheme 4 below).
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • 3-hydroxyproline is reacted with di-tert-butyl dicarbonate (Boc 2 O) in the presence of an organic or inorganic base to provide a Boc-protected amino acid.
  • the transformation is typically carried out in an inert organic solvent, such as tetrahydrofuran (THF), at low temperatures, e.g., from 0 to 25° C., such as 0° C.
  • Suitable organic base includes triethylamine (TEA), and a suitable inorganic base includes sodium bicarbonate.
  • the methyl ester of Boc-protected hydroxyproline carboxylic acid is generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • Inversion of the trans-hydroxy proline to cis-hydroxy proline is achieved by reaction with p-nitrobenzoic acid, phosphine and diisopropyl azodicarboxylate (DIAD) in a suitable solvent such as tetrahydrofuran, dioxane, and alike followed by deacylation with a suitable alkaline reagent such as LiOH in MeOH.
  • a suitable solvent such as tetrahydrofuran, dioxane, and alike
  • a suitable alkaline reagent such as LiOH in MeOH.
  • Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • the substituted proline methyl ester is then treated with hydrochloric acid in dioxane to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt.
  • the deprotection is typically conducted at ambient temperatures (e.g., 0° C.—r.t.) for 4-6 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the coupled product is then converted to the N-benzyloxyamide derivative by treatment with O-benzyl hydroxylamine and trimethyl aluminium in a non-polar organic solvent such as toluene.
  • the reaction is carried out at ambient temperature to 80° C. for about 2 to 8 hours.
  • the N-benzyloxyamide derivative is then converted to the N-hydroxyamide derivative by hydrogenation to remove the benzyloxy protecting group (OBz). Reaction is carried out in a polar organic solvent such as ethanol.
  • the hydrogenation is carried out at in the presence of a palladium (II) catalyst under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 16 hours.
  • the azido functionality can be reduced to the amine in the presence of palladium on carbon.
  • the reaction is carried out in a polar organic solvent such as ethanol.
  • the hydrogentation is carried out at ambient temperatures in 2-3 hours.
  • the sulfonamide is generated in the presence of methanesulfonyl chloride using pyridine as the organic base. Reaction is typically carried out at temperatures in the range of about 0° C. to about 25° C. The reaction is completed in about 24 hours.
  • the sulfonamide bearing methyl ester can be directly converted into the hydroxamate with methanolic hydroxylamine HCl and NaOMe.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • the amine functionality can be transformed to the N-formylated methyl ester in the presence of a mixed anhydride, from formic acid and acetic anhydride.
  • the reaction is carried out at room temperature and is typically completed in 4-24 hours.
  • the N-formylamine bearing methyl ester can be directly converted into the hydroxamate with methanolic hydroxylamine HCl and NaOMe.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • N-formylamine to N-methyl amine is accomplished in the presence of a borane-methylsulfide complex.
  • the reaction is carried out in an inert inorganic solvent like THF.
  • Methanol is added to complete the transformation which is typically carried out at ambient temperatures for about 12 hours.
  • the N-methylamine bearing methyl ester can be directly converted into the hydroxamate with methanolic hydroxylamine HCl and NaOMe.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • the methoxy proline can be generated by alkylating the hydroxyproline in the presence of Methyl iodide and Silver(II) oxide.
  • the reaction is typically carried out in an organic solvent like DMF at ambient temperatures for about 24 hours.
  • the 3-methoxy substituted proline methyl ester is then treated with hydrochloric acid in dioxane to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt.
  • the deprotection is typically conducted at low to ambient temperatures (e.g., 0° C.—r.t.) for 4-6 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the methyl ester can be directly converted into the hydroxamate with methanolic hydroxylamine HCl and NaOMe.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • the hydroxy proline is converted to the fluoroproline by reacting with a fluorinating reagent (dimethylaminosulfurtrifluoride(DAST) in an inert organic solvent like DCM.
  • a fluorinating reagent dimethylaminosulfurtrifluoride(DAST) in an inert organic solvent like DCM.
  • DAST dimethylaminosulfurtrifluoride
  • the reaction is typically initiated at ⁇ 78° C. and progresses at ambient temperatures for about 24 hours.
  • the 3-fluoroproline methyl ester is then treated with hydrochloric acid in dioxane to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt.
  • the deprotection is typically conducted at low to ambient temperatures (e.g., 0° C.—r.t.) for 4-6 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the coupled product is then converted to the N-benzyloxyamide derivative by treatment with O-benzyl hydroxylamine and trimethyl aluminium in a non-polar organic solvent such as toluene.
  • the reaction is carried out at ambient temperature to 80° C. for about 2 to 24 hours.
  • the N-benzyloxyamide derivative is then converted to the N-hydroxyamide derivative by hydrogenation to remove the benzyloxy protecting group (OBz). Reaction is carried out in a polar organic solvent such as ethanol.
  • the hydrogenation is carried out at in the presence of a palladium (II) catalyst under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 16 hours.
  • the methyl ester of hydroxyproline carboxylic acid is generated by alkylation with a suitable methylating reagent such as thionyl chloride and methanol. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • the salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing 1-hydroxybenzotriazole hydrate (HOBT), EDC (carbodiimide), and suitable organic bases like diisopropyethylamine (DIEA).
  • HOBT 1-hydroxybenzotriazole hydrate
  • EDC carbbodiimide
  • DIEA diisopropyethylamine
  • the azide is then converted to the amine by hydrogenation.
  • Reaction is carried out in a solvent mixture such as THF/water/acetic acid.
  • the hydrogenation is carried out at in the presence of 10% palladium on carbon under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 16 hours.
  • the methyl ester can be directly converted into the hydroxamate with a hydroxylamine reagent, such as 50% aqueous (aq). Hydroxylamine in dioxane.
  • a hydroxylamine reagent such as 50% aqueous (aq). Hydroxylamine in dioxane.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • 2-Thiazolidine or 4-thiazolidine carboxylic acid is reacted with di-tert-butyl dicarbonate (Boc 2 O) in the presence of an organic or inorganic base to provide a Boc-protected amino acid.
  • the transformation is typically carried out in an inert organic solvent, such as tetrahydrofuran (THF), at low temperatures, e.g., from 0 to 25° C., such as 0° C.
  • Suitable organic base includes triethylamine (TEA), and a suitable inorganic base includes sodium bicarbonate.
  • the methyl ester of Boc-protected thiazolidine carboxylic acid is generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • the thiazolidine methyl ester is then treated with hydrochloric acid in dioxane to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt.
  • the deprotection is typically conducted at low to ambient temperatures (e.g., 0° C.—r.t.) for 4-6 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the methyl ester can be directly converted into the hydroxamate with a hydroxylamine reagent, such as hydroxylamine hydrochloride and NaOMe.
  • a hydroxylamine reagent such as hydroxylamine hydrochloride and NaOMe.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • the thiazolidine can be oxidized to the sulfoxide in the presence of 3-chloroperoxybenzoic acid (MCPBA) in an inert organic solvent like DCM.
  • MCPBA 3-chloroperoxybenzoic acid
  • the reaction is typically carried out in the range of ⁇ 10° C.-4° C. for 2-3 hours.
  • the sulfone bearing methyl ester can be directly converted into the hydroxamate with a hydroxylamine reagent, such as 50% aqueous (aq). Hydroxylamine in dioxane in the presence of catalytic amounts of KCN. The reaction is carried out at ambient temperature for about 2 to 6 hours.
  • a hydroxylamine reagent such as 50% aqueous (aq). Hydroxylamine in dioxane in the presence of catalytic amounts of KCN.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • 2-Thiazolidine or 4-thiazoilidine carboxylic acid is reacted with di-tert-butyl dicarbonate (Boc2O) in the presence of an organic or inorganic base to provide a Boc-protected amino acid.
  • the transformation is typically carried out in an inert organic solvent, such as tetrahydrofuran (THF), at low temperatures, e.g., from 0 to 25° C., such as 0° C.
  • Suitable organic base includes triethylamine (TEA), and a suitable inorganic base includes sodium bicarbonate.
  • the methyl ester of Boc-protected thiazolidine carboxylic acid is generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
  • the thiazolidine methyl ester is then treated with hydrochloric acid in dioxane to remove the t-butoxycarbonyl protecting group (Boc) and produce the salt.
  • the deprotection is typically conducted at low to ambient temperatures (e.g., 0° C.—r.t.) for 4-6 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the coupled product is then converted to the N-benzyloxyamide derivative by treatment with O-benzyl hydroxylamine hydrochloride and trimethyl aluminium in a non-polar organic solvent such as toluene.
  • the reaction is carried out at ambient temperature to 80° C. for about 2 to 24 hours.
  • the 2-thiazolidine or 4-thiazolidine can be oxidized to the corresponding sulfone in the presence of 3-chloroperoxybenzoic acid (MCPBA) in an inert organic solvent like DCM.
  • MCPBA 3-chloroperoxybenzoic acid
  • the reaction is typically carried out at ambient temperatures for about 24 hours.
  • the N-benzyloxyamide derivative is then converted to the N-hydroxyamide derivative by hydrogenation to remove the benzyloxy protecting group (OBz).
  • Reaction is carried out in a polar organic solvent such as ethanol.
  • the hydrogenation is carried out at in the presence of a palladium (II) catalyst under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 6-8 hours.
  • HCl salt is then condensed with an optionally substituted aromatic carboxylic acids under coupling conditions utilizing O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), diisopropyethylamine (DIEA), in N,N-dimethylformamide (DMF).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropyethylamine
  • the methyl ester can be directly converted into the hydroxamate with a hydroxylamine reagent, hydroxylamine hydrochloride and NaOMe in methanol.
  • the reaction is carried out at ambient temperature for about 2 to 6 hours.
  • methionine or cysteine sulfur can be oxidized to the sulfone in the presence of 3-chloroperoxybenzoic acid (MCPBA) in an inert organic solvent like DCM.
  • MCPBA 3-chloroperoxybenzoic acid
  • the reaction is typically carried out at ambient temperatures for about 24 hours.
  • the methyl ester is then converted to the N-benzyloxyamide derivative by treatment with O-benzyl hydroxylamine hydrochloride and trimethyl aluminium in a non-polar organic solvent such as toluene.
  • the reaction is carried out at ambient temperature to 80° C. for about 2 to 24 hours.
  • the N-benzyloxyamide derivative is then converted to the N-hydroxyamide derivative by hydrogenation to remove the benzyloxy protecting group (OBz).
  • Reaction is carried out in a polar organic solvent such as ethanol.
  • the hydrogenation is carried out at in the presence of a palladium (II) catalyst under hydrogen atmosphere.
  • the hydrogenation conveniently may be carried at ambient temperatures in about 6-8 hours.
  • an aromatic acyl chloride (commercial or generated from respective carboxylic acid, e.g., with oxalyl chloride and catalytic DMF) is reacted with the amino acid (10) in a mixture of organic solvent and water in the presence of inorganic base to provide a amide (11).
  • Suitable inorganic bases include sodium hydroxide, sodium bicarbonate, and the like.
  • Suitable inert organic solvents include dichloromethane, THF, and the like. The reaction conveniently may be conducted at ambient temperature in about 2 to 24 hours.
  • the methyl ester of N-acyl amino acid (11) can be generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperatures, e.g., about 25° C. (Scheme 12). This methyl ester is then converted to the N-hydroxyamide derivative by treatment with aqueous hydroxylamine (e.g., aqueous 50% hydroxylamine) in a polar organic solvent such as dioxane and the like. The reaction is carried out at ambient temperature for about 2 to 6 hours.
  • aqueous hydroxylamine e.g., aqueous 50% hydroxylamine
  • a polar organic solvent such as dioxane and the like.
  • Aromatic acyl chloride (commercial or generated from respective carboxylic acid, e.g., with oxalyl chloride and catalytic DMF) is reacted with the amino acid in a mixture of organic solvent and water in the presence of inorganic base to provide a amide utilizing a suitable inorganic base like sodium hydroxide.
  • the reaction is carried out in an inert organic solvent like dichloromethane. The reaction may be conducted at ambient temperature in about 2 to 24 hours.
  • the methyl ester of N-acyl amino acid can be generated by alkylation with a suitable methylating reagent such as trimethylsilyl-diazomethane. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperatures, e.g., about 25° C. This methyl ester is then converted to the N-hydroxyamide derivative by treatment with aqueous hydroxylamine (e.g., aqueous 50% hydroxylamine) in a polar organic solvent such as dioxane. The reaction is carried out at ambient temperature for about 2 to 6 hours.
  • aqueous hydroxylamine e.g., aqueous 50% hydroxylamine
  • compositions that can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of bacterial infections.
  • a therapeutically effective dose or amount refers to that amount of one or more compounds described herein sufficient to result in amelioration of symptoms of the infection.
  • the pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others.
  • compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection.
  • the compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive.
  • Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl cellulose, and/or polyvinylpyrrolidone.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which can contain an inactive diluent, such as water.
  • Pharmaceutical formulations can be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.
  • suspensions can include oils.
  • oils include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil and mixtures of oils.
  • Suspension preparation can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations can include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations.
  • the pharmaceutical formulations can be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailablity modifiers and combinations of these.
  • a propellant for an aerosol formulation can include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • the compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Generally, the oil or fatty acid is non volatile, including natural or synthetic oils, fatty acids, mono, di or tri glycerides.
  • the pharmaceutical formulation can be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi dose containers.
  • the pharmaceutical formulations can be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • suspension formulations which can also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991).
  • the formulations of the invention can be designed for to be short acting, fast releasing, long acting, and sustained releasing.
  • the pharmaceutical formulations can also be formulated for controlled release or for slow release.
  • compositions can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers.
  • compositions can contain, for example, from about 0.1% by weight, to about 90% or more by weight, of the active material, depending on the method of administration.
  • each unit can contain, for example, from about 5 to 500 mg or more of the active ingredient.
  • the dosage as employed for adult human treatment can range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration.
  • Specific dosages can be adjusted depending on conditions of infection, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • the total daily dose can typically range from about 0.1 mg/kg/day to about 500 mg/kg/day in single or in divided doses.
  • dosages for humans can range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
  • a therapeutically effective dose or amount can vary depending upon the route of administration and dosage form.
  • Some compositions of the instant invention provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.
  • the invention provides methods of treating or preventing a bacterial infection in a subject, such as a mammal, e.g., a human or non human mammal, comprising administering an effective amount of one or more compounds described herein to the subject.
  • Suitable subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cynomolgus (also known as crab eating or long tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like.
  • the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
  • the compounds described herein can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms, including infections by pathogenic bacterial species. Infections of Gram negative aerobic and anaerobic bacteria that may be treated include those set forth in Example A.
  • Infections that can be treated with the described compounds include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, bacteremia, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. These infections can be treated in hospital or community settings via various routes of administration as described herein.
  • the compounds or compositions described herein can also be used prophylactically.
  • the compounds or compositions described herein can also be used empirically, i.e. when a patient exhibits symptoms consistent with an infection, but a true infection has not yet diagnosed, for example by blood tests. Accordingly, one or more of the present compounds or compositions can be administered to an individual deemed to be at risk for developing a microbial infection or having conditions consistent with a microbial infection.
  • Individuals at risk for developing a microbial infection include individuals who have been exposed to a particular microorganism, such as a pathogenic bacterial species; individuals having a compromised immune system, such as individuals suffering from an immunodeficiency disease or taking immunocompromising medication; patients on antimicrobial therapy and individuals having a history of repeated or chronic infection, such as children who have repeated infections of the middle ear.
  • a particular microorganism such as a pathogenic bacterial species
  • individuals having a compromised immune system such as individuals suffering from an immunodeficiency disease or taking immunocompromising medication
  • patients on antimicrobial therapy and individuals having a history of repeated or chronic infection such as children who have repeated infections of the middle ear.
  • Another embodiment provides a method of killing or preventing the growth of bacteria that includes contacting a bacteria with either a non-therapeutic amount or a therapeutically effective amount of one or more of the present compounds.
  • Such methods can occur in vivo or in vitro.
  • In vitro contact can involve a screening assay to determine the efficacy of the one or more compounds against selected bacteria at various amounts or concentrations.
  • In vivo contact with a therapeutically effective amount of the one or more compounds can involve treatment or prophylaxis of a bacterial infection in the animal in which the contact occurs. The effect of the one or more compounds on the bacteria and/or host animal can also be determined or measured.
  • isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • the present invention also covers the individual isomers of the compounds represented by the formulas herein as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • Stereoisomeric mixtures e.g. mixtures of diastereomers
  • Diastereomeric mixtures for example can be separated into their individual diastereomers by means of fraction crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds or in a compound of formula I itself.
  • Enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by HPLC, using chiral chromatographic media.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the aqueous layer was acidified with 6N HCl and extracted with DCM (2 ⁇ ) and once with n-butanol. All organic extracts were combined, concentrated, and co-evaporated with toluene. The residue was then dried under high vacuum to give the desired Boc-protected carboxylic acid.
  • Method B The Boc-protected acid (7.35 mmol, 1 eq.) was taken into THF-MeOH (1:1) and the reaction cooled to 0° C. 2M TMSCHN 2 in ether (7.35 ml, 2 eq.) was added with stirring in one portion, and the reaction stirred at 0° C. for 2 h. The reaction was monitored by thin layer chromatography (TLC) (eluent: 4:1 hexanes-ethyl acetate). Solvent was removed under vacuum. The residue was purified by SiO 2 column chromatography (gradient 20%-40% ethyl acetate in hexanes) to provide the desired methyl ester.
  • TLC thin layer chromatography
  • Method D The cis-O-benzoyl protected methyl ester was taken into MeOH and 0.5M sodium methoxide was added with stirring at 0° C. The reaction was stirred at rt for 2 h. It was then neutralized with Amberlite H+ resin, filtered, concentrated under high pressure and purified by SiO 2 column chromatography (gradient 10-20% acetone in DCM) to give the corresponding cis-3-hydroxyproline methyl ester.
  • Method F The Boc-protected methyl ester was taken into excess 4M HCl/dioxane (25 ml) and the reaction stirred at rt for 4 h. It was then concentrated, and the residue triturated with ether to precipitate the desired hydrochloric acid salt. This salt was dried under high vacuum.
  • Method G Carboxylic acid (0.91 mmol), DMF (20 mL), and DIEA (0.64 ml, 3.67 mmol) are combined and stirred at rt. Amine (1.19 mmol) and HATU (451 mg, 1.19 mmol) are added to the stirring mixture. The combined mixture is stirred for 18 h. Ethyl acetate (100 ml) is added. The diluted mixture is washed consecutively with 10% citric acid solution, brine, saturated sodium bicarbonate solution, and again with brine. The ethyl acetate layer is dried over sodium sulfate and concentrated in vacuo. The crude product is used in the next reaction without further purification. In cases where purification was performed, the compounds were purified by column chromatography (SiO 2 , gradient 30-40% ethyl acetate/hexanes).
  • Method H Methyl ester (0.76 mmol), hydroxylamine hydrochloride (524 mg, 7.54 mmol), and MeOH are stirred at rt. Sodium methoxide (98%, 499 mg, 9.05 mmol) is added, and the reaction is monitored by HPLC. If the reaction is not completed within 2 h, an additional charge of sodium methoxide (98%, 499 mg, 9.05 mmol) is added and the reaction is monitored again by HPLC. The crude mixture is concentrated, dissolved in dimethyl sulfoxide (DMSO), and purified by preparative-HPLC.
  • DMSO dimethyl sulfoxide
  • Method I 2M Trimethylaluminium in toluene (4 eq.) was slowly added to a suspension of the O-benzylhydroxylamine hydrochloride (4 eq.) in toluene at 0° C. under nitrogen. The reaction was brought to rt slowly and stirred for 1 h. This mixture was then added to a solution of the methyl ester # (1 eq.) in toluene at rt. The combined mixture was heated at 54° C. for 1-2 h, and the reaction was monitored by TLC (7:3 hexanes/ethyl acetate).
  • Method J To a solution of the protected hydroxamate (1.37 mmol) in ethanol (25 ml) under a nitrogen atmosphere, 10%/wt of 10% Pd/C (70 mg) was added and the reaction evacuated and stabilized to a hydrogen atmosphere. The reaction was stirred for 12 h, filtered through a pad of Celite and the filtrate concentrated to provide the desired final inhibitor.
  • Method K To a solution of the methyl ester (8.93 mmol) in ethanol (50 ml), with small amounts of MeOH to dissolve the compound, under a nitrogen atmosphere, 10% Pd/C (350-400 mg; ca. 10% weight of the substrate) was added and the reaction evacuated and stabilized to a hydrogen atmosphere. The reaction is stirred for 2-3 h, filtered through a pad of Celite and the filtrate concentrated to provide the desired free amine compound.
  • Method M A 5:1 mixture of formic acid and acetic anhydride was heated at 60° C. for 1-1.5 h. The mixture was cooled and added to the 3-aminoproline intermediate, and the mixture stirred for 8-24 h. The reaction was monitored by HPLC. It was concentrated under vacuum, co-evaporated with toluene and DCM, and the residue purified by column chromatography (SiO 2 , gradient 0-30% acetone/DCM, then 2.5%-5% MeOH/DCM) to provide the N-formyl compound.
  • Method N A solution of the N-formyl intermediate (1.78 mmol, 1 eq.) in tetrahydrofuran was cooled to 0° C.
  • Commercially available borane-methylsulfide complex (3.36 mmol, 2 eq.) was added drop-wise and the mixture stirred at rt for 5 h. It was then quenched with MeOH (15 ml) and stirred at rt for an additional 16 h. 2M HCl/MeOH was added, and the reaction mixture refluxed for 3 h. The reaction was concentrated, and excess DCM was added. Under stirring conditions at 0° C. sodium bicarbonate was slowly added till the ph of the reaction was ⁇ 8.
  • Method P To a solution of the protected hydroxamate (0.65 mmol) in ethanol (25 ml) under a nitrogen atmosphere, 10%/wt of 10% Pd(OH) 2 /C was added, and the reaction vessel was charged with hydrogen. The reaction was stirred for 8 h, filtered through a pad of Celite, and the filtrate concentrated to provide the desired final inhibitor.
  • Method R HPLC analysis conditions are as follows. YMC-Pak Pro C18, S-3 ⁇ m, 120A, 50 ⁇ 4.6 mm I.D. Column; gradient eluent 0%-90% MeCN in water (both solvents containing 0.1% TFA) over 8.5 min, 1.5 mL/min.
  • Method S The methyl ester (1 eq.) was taken into DCM and the reaction was cooled to 40° C. MCPBA (2 eq.) in DCM was added very slowly. The temperature of the reaction was maintained below ⁇ 5° C. for 2 h during which the reaction was monitored for completion by TLC in hexanes/ethyl acetate (2:3). The reaction provided both the sulfone and the sulfoxide intermediates. Upon completion, excess DCM was added to the reaction mixture and washed with cold saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography (SiO 2 , hexanes/ethyl acetate and acetone/DCM) to afford the desired oxidized intermediate(s).
  • Method T The methyl ester was taken into a mixture of THF-MeOH (1:1 volume by volume). 50% aq. hydroxylamine/water followed by catalytic amounts of potassium cyanide was then added to the reaction mixture. The reaction was allowed to stir at rt for 16 h. Solvents were removed under vacuum, and the residue was taken into water and the compound extracted into the ethyl acetate layer. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by preparative HPLC to give the final inhibitor.
  • Method U A solution of anhydrous DMSO (22.7 mL, 320 mmol) in anhydrous DCM (600 mL) is stirred at ⁇ 78° C. under nitrogen. Oxalyl chloride (13.9 mL, 159 mmol) is slowly added at a rate to maintain a temperature below ⁇ 65° C. The mixture is stirred for an additional 15 min, and alcohol (126 mmol) in DCM (125 mL) is added. After an additional 30 min of stirring, triethylamine (85.0 mL, 610 mmol) is added. The mixture is stirred while slowly warming to rt (ca. 80 min). This is diluted with DCM and washed with 10% citric acid solution.
  • the DCM layer is separated, washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product is purified by column chromatography (SiO 2 , 30%-50% ethyl acetate in hexanes).
  • Method W Alkene (0.362 mmol), 4-methylmorpholine N-oxide (47 mg, 0.401 mmol), 2.5% OsO 4 in tert-butyl alcohol (t-BuOH) (0.46 mL, 0.037 mmol), acetone (4 mL), and water (0.25 mL) were combined and stirred at rt for 18 h. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (10% MeOH in DCM).
  • Method X Alcohol (1.62 mmol), 2,6-di-tert-butyl-4-methylpyridine (664 mg, 3.23 mmole), and anhydrous DCM (10 mL) are combined and stirred at 4° C. Trimethyloxonium tetrafluoroborate (239 mg, 1.62 mmole) is added to the reaction mixture, and the combination mixture is stirred for 1 h at 4° C. The mixture is warmed to room temperature and allowed to stir for an additional 4 h. The mixture is diluted with DCM and washed with saturated, aqueous NaHCO 3 solution. The organic layer is dried over sodium sulfate, and concentrated under vacuum. The crude material is purified by column chromatography (3% MeOH in DCM).
  • Method Z An appropriate O-benzyl, N-benzyl or N-benzyl carbamate (0.311 mmol), 10% Pd on carbon (33 mg, 0.031 mmol), and EtOH (5 mL) are combined and stirred under H 2 at rt for 8 h. The mixture was filtered through Celite and concentrated in vacuo. The crude material is used in the next reaction without further purification, unless specifically stated.
  • Method BB Methyl ester (54.63 mmol), NaOH (54.74 mmol), water (300 mL), and MeOH (300 mL) are combined and stirred at 4° C. for 18 h.
  • the aqueous layer is washed with ether.
  • the extracted aqueous layer is acidified to pH 1 with 1 N HCl.
  • the acidic solution is extracted with ethyl acetate.
  • the ethyl acetate layer is dried over sodium sulfate, concentrated in vacuo, and used in the next step without further purification.
  • Method CC Alkene (1.14 mmol), MCPBA (77% max, 2.28 mmol), and DCM (50 mL) are combined and stirred at 4° C. The reaction is slowly warmed to rt, and then stirred at rt for and additional 18 h. The reaction mixture is concentrated in vacuo, and purified by column chromatography (SiO 2 , 0-20% MeOH in DCM). Two separate diastereomeric epoxides are obtained.
  • Method DD Epoxide (0.74 mmol), sodium azide (1.45 g, 22.26 mmol), DMF (10 mL), and water (2 mL) are combined and stirred at 80° C. for 18 h. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The compound was used in the next reaction without further purification.
  • Method EE 4-(4-n-Propylphenyl)benzoic acid (130 mg, 0.53 mmol), DCM (8 ml), DMF (1 drop), and oxalyl chloride (0.09 ml, 1.03 mmol) are combined and stirred at rt for 1 h.
  • the reaction mixture is concentrated in vacuo, and the residue is redissolved in DCM (8 mL).
  • the amine (0.47 mmol) is dissolved in pyridine and combined with the DCM mixture.
  • the combined mixture is stirred at rt for 18 h, and diluted with ethyl acetate.
  • the ethyl acetate solution is washed with water, dried over sodium sulfate, and concentrated in vacuo. The compound was used in the next reaction without further purification.
  • Method FF To a stirred solution or suspension of the acid (1 mmol, 1 eq) in DCM (3-5 mL) was added few drops of DMF. The resulting solution was cooled to 0° C. in ice bath followed by addition of 2M (COCl) 2 in toluene (1 mL, 2 eq.). This mixture was stirred at 0° C. for 3 h, and solvents were removed under vacuum to yield relatively pure acid chloride. The residue was suspended in anhydrous THF (2-3 mL), and resulting suspension was cooled to 0° C. To this suspension was added amino acid (0.5 mmol) dissolved in 1N NaOH solution (1-2 mL).
  • Method GG To a stirred solution of above ester (1 mmol) in MeOH (3-5 mL) was added a 50% aq. solution of NH 2 OH (1-2 mL). This mixture was stirred at rt for 30 min to 16 h, at which time the reaction was complete as detected by HPLC. The reaction was concentrated under reduced pressure and the resulting residue was suspended in MeOH/water to prepare a clear solution. This solution was then purified via preparative HPLC to yield the pure product.
  • Method HH HPLC analysis conditions are as follows. YMC-Pak Pro C18, S-3 ⁇ m, 120A, 50 ⁇ 4.6 mm I.D. Column; gradient eluent 2%-98% MeCN in water (both solvents containing 0.1% TFA) over 5 min, 2.0 mL/min.
  • HPLC analysis conditions are as follows. YMC-Pak Pro C18, S-3 ⁇ m, 120A, 50 ⁇ 4.6 mm I.D. Column; gradient eluent 2%-98% MeCN in water (both solvents containing 0.1% TFA) over 6 min, 1.5 mL/min.
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.10 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 N 4 O 4 (270.29). Found: 271.4 [M+H].
  • Step 4 (2S,3S)-Methyl 3-azidopyrrolidine-2-carboxylate hydrochloride salt was prepared from (2S,3S)-1-tert-butyl 2-methyl 3-azidopyrrolidine-1,2-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 6 H 10 N 4 O 2 (170.29). Found: 171.2.
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 N 4 O 4 (270.29). Found: 271.4 [M+H].
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 N 4 O 4 (270.29). Found: 271.4 [M+H].
  • Step 4 (2S,3S)-Methyl 3-azidopyrrolidine-2-carboxylate hydrochloride salt was prepared from (2S,3S)-1-tert-butyl 2-methyl 3-azidopyrrolidine-1,2-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 6 H 10 N 4 O 2 (170.29). Found: 171.2
  • Step 6 (2S,3S)-Methyl-3-amino-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate was prepared from (2S,3S)-methyl 3-azido-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate following Method K (quantitative yield).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 N 4 O 4 (270.29). Found: 271.4 [M+H].
  • ES ⁇ MS calcd. for C 6 H 10 N 4 O2 (170.29). Found: 171.2.
  • Step 6 (2S,3S)-Methyl-3-amino-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate was prepared from (2S,3S)-methyl 3-azido-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate following Method K (quantitative yield).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 N 4 O 4 (270.29). Found: 271.4 [M+H].
  • Step 4 (2S,3S)-Methyl 3-azidopyrrolidine-2-carboxylate hydrochloride salt was prepared from (2S,3S)-1-tert-butyl 2-methyl 3-azidopyrrolidine-1,2-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 6 H 10 N 4 O 2 (170.29). Found: 171.2.
  • Step 6 (2S,3S)-Methyl-3-amino-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate was prepared from (2S,3S)-methyl 3-azido-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate following Method K (quantitative yield).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • ES ⁇ MS calcd. for C 11 H 18 FNO 4 (247.26).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • Step 4 (2S,3S)-Methyl 3-methoxypyrrolidine-2-carboxylate hydrochloride salt was prepared from (2S,3S)-1-tert-butyl 2-methyl 3-methoxypyrrolidine-1,2-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 7 H 13 NO 3 (159.18). Found: 160.4 [M+H].
  • Step 5 (2S,3S)-Methyl 3-methoxy-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxylate was prepared from (2S,3S)-methyl 3-methoxypyrrolidine-2-carboxylate hydrochloride salt and 4-(p-n-propylphenyl)-benzoic acid following Method G (quantitative yield).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • Step 6 (2S,3R)-Methyl 3-methoxypyrrolidine-2-carboxylate hydrochloride salt was prepared from (2S,3R)-1-tert-butyl 2-methyl 3-methoxypyrrolidine-1,2-dicarboxylate following Method F (quantitative yield).
  • Step 1 DMSO, oxalyl chloride, Et 3 N, DCM, ⁇ 78° C. to rt, 125 min;
  • Step 2 Cp 2 ZrCl 2 , CH 2 Br 2 , Zn, THF, rt to 30° C., 3 h;
  • Step 3 OsO 4 , 4-methylmorpholin N-oxide (NMO), t-BuOH, acetone, water, rt, 18 h;
  • Step 4 (CH 3 ) 3 OBF 4 , 2,6-di-tert-butyl-4-methylpyridine, DCM, 4° C.
  • Step 5 LiOH, MeOH, water, reflux, 1 h;
  • Step 6 HATU, DIEA, DMF, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, rt, 18 h;
  • Step 7 10% Pd/C, EtOH, H 2 , rt, 8 h;
  • Step 8 4-(4-n-propylphenyl)benzoic acid, oxalyl chloride, DMF, DCM, rt, 1 h; then DCM, pyridine, rt, 18 h;
  • Step 9 TFA, DCM, rt, 2 h.
  • 1H NMR 300 MHz, CDCl 3 ) ⁇ 7.42-7.29 (m, 5H), 5.20-5.09 (m, 2H), 4.94-4.81 (m, 1H), 4.07-3.59 (m, 5H), 3.04-2.87 (m, 1H), 2.67-2.56 (m, 1H).
  • 1H NMR 300 MHz, CDCl 3 ) ⁇ 7.42-7.23 (m, 5H), 5.24-4.97 (m, 4H), 4.63-4.48 (m, 1H), 4.22-4.10 (m, 2H), 3.78-3.56 (m, 3H), 3.07-2.88 (m, 1H), 2.72-2.58 (m, 1H).
  • 1H NMR 300 MHz, CDCl 3 ) ⁇ 7.40-7.24 (m, 5H), 5.22-4.96 (m, 2H), 4.61-4.42 (m, 1H), 3.82-3.44 (m, 7H), 2.37-1.86 (m, 2H); ESI(+) calcd. for C 15 H 19 NNaO 6 (332.11). Found 332.5.
  • 1H NMR 300 MHz, CDCl 3 ) ⁇ 7.40-7.21 (m, 5H), 5.32-4.97 (m, 2H), 4.61-4.42 (m, 1H), 3.80-3.28 (m, 10H), 2.69-1.87 (m, 2H).
  • 1H NMR 300 MHz, CDCl 3 ) ⁇ 7.40-7.18 (m, 5H), 5.23-5.05 (m, 2H), 4.65-4.47 (m, 1H), 3.78-3.28 (m, 7H), 2.46-1.97 (m, 3H).
  • ESI(+) calcd. for C 12 H 23 N 2 O 5 (275.16). Found 275.2.
  • ESI( ⁇ ) calcd. for C 28 H 35 N 2 O 6 (495.25). Found 495.2.
  • Step 1 O-benylhydroxylamine, HATU, DIEA, DMF, rt, 18 h;
  • Step 2 OsO 4 , NMO, t-BuOH, acetone, water, rt, 18 h;
  • Step 3 TFA, DCM, rt, 2 h;
  • Step 4 4-(4-n-propylphenyl)benzoic acid, HATU, DIEA, DMF, rt, 18 h;
  • Step 5 10% Pd/C, EtOH, H 2 , rt, 8 h.
  • Step 1 (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G.
  • 1H NMR 300 MHz, CHCl 3 ) ⁇ 9.79 (s, 1H), 7.48-7.28 (m, 5H), 5.01-4.83 (m, 2H), 4.47-3.41 (m, 5H), 1.83-1.28 (m, 11H).
  • ESI(+) calcd. for C 12 H 17 N 2 O 4 (253.12). Found 253.2.
  • Step 5 (2S,3R,4S)—N,3,4-Trihydroxy-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxamide is prepared from (2S,3R,4S)—N-(benzyloxy)-3,4-dihydroxy-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxamide following Method Z.
  • Step 1 O-benylhydroxylamine, HATU, DIEA, DMF, rt, 18 h;
  • Step 2 MCPBA, DCM, 0° C. to rt, 18 h;
  • Step 3 sodium azide, DMF, water, 80° C., 18 h;
  • Step 4 TFA, DCM, rt, 2 h;
  • Step 5 4-(4-n-propylphenyl)benzoic acid, HATU, DIEA, DMF, rt, 18 h;
  • Step 6 10% Pd/C, EtOH, H 2 , rt, 8 h.
  • 1H NMR 300 MHz, CHCl 3
  • ⁇ 9.83-9.00 (m, 1H), 8.14-7.26 (m, 5H), 5.22-4.79 (m, 2H); 4.54-3.24 (m, 5H), 1.38 (s, 9H);
  • ESI( ⁇ ) calcd. for C 17 H 21 N 2 O 5 (333.15). Found 333.2
  • ESI(+) calcd. for C 12 H 16 N 5 O 3 (287.13). Found 287.2.
  • ESI( ⁇ ) calcd. for C 28 H 28 N 5 O 4 (498.21). Found 498.2.
  • Step 6 (2S,3S,4R)-4-Amino-N,3-dihydroxy-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxamide is prepared from (2S,3R,4R)-4-azido-N-(benzyloxy)-3-hydroxy-1-(4′-propylbiphenylcarbonyl)pyrrolidine-2-carboxamide following Method Z.
  • ESI(+) calcd. for C 12 H 16 N 5 O 3 (287.13). Found 287.2.
  • ESI( ⁇ ) calcd. for C 28 H 28 N 5 O 4 (498.21). Found 498.2.
  • ES ⁇ MS calcd. for C 10 H 17 NO 4 S (247.31).
  • Step 2 (S)-Methyl thiazolidine-2-carboxylate hydrochloride salt was prepared from (S)-3-tert-butyl 2-methyl thiazolidine-2,3-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1[M+H].
  • ES ⁇ MS calcd. for C 10 H 17 NO 4 S (247.31).
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1[M+H].
  • ES ⁇ MS calcd. for C 10 H 17 NO 4 S (247.31).
  • Step 2 (S)-Methyl thiazolidine-2-carboxylate hydrochloride salt was prepared from (S)-3-tert-butyl 2-methyl thiazolidine-2,3-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1[M+H].
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1 [M+H].
  • Step 1 (S)-3-tert-Butyl 4-methyl thiazolidine-3,4-dicarboxylate was prepared from (S)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid following Method B using the commercially available Boc-protected carboxylic acid (yield 92%).
  • Step 2 (S)-Methyl thiazolidine-4-carboxylate hydrochloride salt was prepared from (S)-3-tert-butyl 4-methyl thiazolidine-3,4-dicarboxylate following Method F (quantitative yield).
  • 1H NMR (DMSO-d6) 5.43-5.37 (d, 1H), 3.96 (bs, 2H), 3.87 (s, 2H), 3.27 (bs, 2H), 1.59-1.53 (d, 9H).
  • HPLC: Rt 5.31 (d, 1H)
  • ES ⁇ MS calcd. for C 10 H 17 NO 4 S (247.09). Found: 269.9 [M+Na].
  • Step 2 (R)-Methyl thiazolidine-2-carboxylate hydrochloride salt was prepared from (R)-3-tert-butyl 2-methyl thiazolidine-2,3-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1[M+H].
  • Step 2 (R)-Methyl thiazolidine-2-carboxylate hydrochloride salt was prepared from (R)-3-tert-butyl 2-methyl thiazolidine-2,3-dicarboxylate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 9 NO 2 S (147.2). Found: 148.1 [M+H].
  • HPLC: Rt 6.90 min following Method R.
  • ES ⁇ MS calcd. for C 27 H 28 N 2 O 5 S (492.59). Found: 491.2 [M ⁇ H].
  • 1H NMR 300 MHz, CDCl 3 ); 7.98-7.89 (m, 2H), 7.65-7.61 (m, 2H), 7.14-7.07 (m, 2H), 6.88-6.79 (m, 2H), 5.60-5.54 (m, 1H), 3.90 (s, 3H).
  • DL-methyl-3,3,3-triflurobiphenyl-4-ylcarboxamido)propanoate is prepared from 3,3,3-trifluoro-D,L-alanine and 4′-fluoro-biphenyl-4-carboxylic acid following Method FF. This material was used without any further purification.
  • the methyl ester was available commercially.
  • ES ⁇ MS calcd. for C 10 H 19 NO 4 S (249.1). Found: 272 [M+Na].
  • Step 2 (S)-Methyl 2-amino-3-(methylthio)propanoate hydrochloride salt was prepared from (S)-methyl 2-(3,3-dimethylbutanamido)-3-(methylthio)propanoate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 11 NO 2 S (149.05). Found: 150.2 [M+H].
  • Step 2 (S)-Methyl 2-amino-3-(methylthio)propanoate hydrochloride salt was prepared from (S)-methyl 2-(3,3-dimethylbutanamido)-3-(methylthio)propanoate following Method F (quantitative yield).
  • ES ⁇ MS calcd. for C 5 H 11 NO 2 S (149.05). Found: 150.2 [M+H].
  • Step 1 4-(4-n-propylphenyl)benzoic acid, HATU, DIEA, DMF, rt, 18 h;
  • Step 2 hydroxylamine hydrochloride, MeOH, NaOMe, rt, 2 h.
  • Step 1 DIAD, Ph 3 P, THF, ⁇ 78° C., 3 h 50 min;
  • Step 2 pyrazole, acetonitrile (ACN), 55° C., 24 h;
  • Step 3 HATU, DIEA, DMF, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, rt, 18 h;
  • Step 4 10% Pd/C, EtOH, H 2 , rt, 8 h;
  • Step 5 4-(4-n-propylphenyl)benzoic acid, HATU, DIEA, DMF, rt, 18 h;
  • Step 6 TFA, DCM, rt, 2 h.
  • Step 1 (Steps 1 and 2 are done similar to that described in Organic Syntheses, Coll. Vol. 9, p. 58-63)
  • DIAD (20.8 mL, 106 mmol) was added dropwise.
  • the mixture is stirred at ⁇ 78° C. for 20 min.
  • a solution of N-(benzyloxycarbonyl)-L-serine (25.3 g, 106 mmol) in THF (150 mL) is added to the reaction mixture.
  • Step 2 N-(Benzyloxycarbonyl)-L-serine p-lactone (1.5 g, 6.8 mmol), pyrazole (0.49 g, 7.2 mmol), and acetonitrile (25 mL) are combined and stirred for 12 h at 55° C. An additional charge of pyrazole (0.25 g, 3.6 mmol) is added to the reaction and stirred for an additional 12 h. The reaction mixture is concentrated in vacuo. The residue is dissolved in sodium hydroxide solution (1 M), and washed with DCM.
  • Step 3 (2S)-Tetrahydro-2H-pyran-2-yl 2-(benzyloxycarbonylamino)-3-(1H-imidazol-1-yl)propanoate is prepared from N-(benzyloxycarbonyl)-p-(pyrazol-1-yl)-L-alanine and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine following Method G.
  • ESI(+) calcd. for C 19 H 25 N 4 O 5 (389.18). Found 389.2.
  • Step 4 (2S)-Tetrahydro-2H-pyran-2-yl 2-amino-3-(1H-imidazol-1-yl)propanoate is prepared from (2S)-tetrahydro-2H-pyran-2-yl 2-(benzyloxycarbonylamino)-3-(1H-imidazol-1-yl)propanoate following Method Z.
  • ESI( ⁇ ) calcd. for C 11 H 17 N 4 O 3 (253.13). Found 253.2.
  • Step 5 (2S)-Tetrahydro-2H-pyran-2-yl 3-(1H-imidazol-1-yl)-2-(4′-propylbiphenyl-4-ylcarboxamido)propanoate is prepared from (2S)-tetrahydro-2H-pyran-2-yl 2-amino-3-(1H-imidazol-1-yl)propanoate and 4-(4-propylphenyl)benzoic acid following Method G. ESI(+) calcd. for C 27 H 33 N 4 O 4 (477.25). Found 477.1.
  • Step 6 (S)-3-(1H-imidazol-1-yl)-2-(4′-propylbiphenyl-4-ylcarboxamido)propanoic acid is prepared from (2S)-tetrahydro-2H-pyran-2-yl 3-(1H-imidazol-1-yl)-2-(4′-propylbiphenyl-4-ylcarboxamido)propanoate following Method AA. The compound is dissolved in DMSO, and purified by preparative-HPLC (yield—6%).
  • Step 1 NaOH water, MeOH, 4° C., 18 h
  • Step 2 HATU, DIEA, DMF, 3-(trifluoromethylthio) aniline, rt, 18 h
  • Step 3 hydroxylamine hydrochloride, MeOH, NaOMe, rt, 2 h.
  • 1H NMR 300 MHz, DMSO-d6) ⁇ 8.40-8.28 (m, 2H), 3.78 (s, 3H).
  • 1H NMR 300 MHz, CHCl 3 ) ⁇ 11.66 (s, 1H), 8.29 (s, 1H), 8.22-8.09 (m, 1H), 7.96-7.82 (m, 2H), 7.50-7.37 (m, 2H), 3.99 (s, 3H); ESI( ⁇ ) calcd. for C 14 H 9 F 3 NO 4 S (344.02). Found 344.0
  • 1H NMR 300 MHz, DMSO-d6) ⁇ 12.22 (s, 1H), 11.61 (s, 1H), 9.54 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.84-7.39 (m, 3); ESI( ⁇ ) calcd. for C 13 H 8 F 3 N 2 O 4 S (345.02). Found 345.0.
  • 1H NMR (DMSO-d6) 5.29-5.22 (bs, 1H), 4.52 (bs, 2H), 3.64-3.52 (m, 2H), 1.55 (bs, 9H).
  • ES ⁇ MS calcd. for C 9 H 15 NO 4 S (233.07). Found: 256.2 [M+Na].
  • 1H NMR (DMSO-d6) 11.474 (bs, 1H), 7.6-7.55 (m, 5H), 4.97 (bs, 1H), 3.94-3.8 (m, 2H), 3.44-3.23 (m, 2H), 1.58-1.53 (m, 9H).
  • ES ⁇ MS calcd. for C 16 H 22 N 2 O 4 S (338.13). Found: 337.2 [M ⁇ H].
  • Step 3 (S)—N-(Benzyloxy)thiazolidine-2-carboxamide hydrochloride salt was prepared from (S)-tert-butyl 2-(benzyloxycarbamoyl)thiazolidine-3-carboxylate following Method F (quantitative yield) 1H NMR (DMSO-d6): 11.91 (bs, 1H), 7.4-7.33 (m, 5H), 5.07 (s, 1H), 4.82 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.46 (m, 2H), 3.2-3.15 (m, 2H).
  • ES ⁇ MS calcd. for C 11 H 14 N 2 O 2 S (238.08). Found: 239.1 [M+H].
  • Step 1 To a stirred 0° C. suspension of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (5.1 g, 38.9 mmol, Acros) in anhydrous MeOH (100 mL) was added dropwise SOCl 2 (5.6 mL, 77.2 mmol) after 1 h dissolution of starting material was complete. The reaction mixture was stirred at rt 24 h then evaporated under reduced pressure. The resulting residue was triturated with anhydrous Et 2 O, filtered, washed with additional Et 2 O and dried in vacuo to furnish the product (7.1 g, quantitative yield). ES+MS: calcd. for C 6 H 11 NO 3 (145.07). Found: 146.0 [M+H].
  • Step 2 To a stirred 0° C. suspension of (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 11.0 mmol), 4′-ethylbiphenylcarboxylate (2.74 g, 12.1 mmol, Acros), HOBt (1.63 g, 12.1 mmol) and DIEA (3.71 mL, 22.0 mmol), in anhydrous DCM (50 mL) was added EDC (2.6 g, 13.8 mmol) in small portions over 5′.
  • Step 3 To a stirred 0° C. solution of (2S,3S)-methyl-3-hydroxy-1-(4′-ethylbiphenylcarbonyl) pyrrolidine-2-carboxylate (1.0 g, 2.83 mmol) and TPP (0.82 g, 3.53 mmol) in anhydrous THF (10 mL) was added DPPA (765 ⁇ L, 3.53 mmol) followed by DIAD (915 ⁇ L, 4.41 mmol) added dropwise over 5′. The reaction mixture was warmed to rt over 1 h and stirred 20 h then evaporated on to silica under reduced pressure.
  • Step 4 A solution of (2S,3R)-methyl-3-azido-1-(4′-ethylbiphenylcarbonyl)pyrrolidine-2-carboxylate (300 mg, 0.793 mmol) in THF/H 2 O/AcOH, 4:1:1 (6 mL) was added to 10% Pd/C Degussa 50% w/w wet form (150 mg). The reaction mixture was shaken under 35 psi H 2 atmosphere for 5 h then filtered through celite and evaporated under reduced pressure. The resulting residue was lyophilized from MeCN/H 2 O 1:1 to furnish the product (311 mg, 95% yield).
  • Step 5 (2S,3R)-3-Amino-N-hydroxy-1-(4′-ethylbiphenylcarbonyl)pyrrolidine-2-carborxamide was prepared from (2S,3R)-methyl-3-amino-1-(4′-ethylbiphenylcarbonyl)pyrrolidine-2-carboxylate by Method GG.
  • 1H NMR (DMSO-d6) 5.29-5.22 (bs, 1H), 4.52 (bs, 2H), 3.64-3.52 (m, 2H), 1.55 (bs, 9H).
  • ES ⁇ MS calcd. for C 9 H 15 NO 4 S (233.07). Found: 256.2 [M+Na].
  • 1H NMR (DMSO-d6) 11.474 (bs, 1H), 7.6-7.55 (m, 5H), 4.97 (bs, 1H), 3.94-3.8 (m, 2H), 3.44-3.23 (m, 2H), 1.58-1.53 (m, 9H).
  • ES ⁇ MS calcd. for C 16 H 22 N 2 O 4 S (338.13). Found: 337.2 [M ⁇ H].
  • Step 3 (S)—N-(Benzyloxy)thiazolidine-2-carboxamide hydrochloride salt was prepared from (S)-tert-butyl 2-(benzyloxycarbamoyl)thiazolidine-3-carboxylate following Method F (quantitative yield) 1H NMR (DMSO-d6): 11.91 (bs, 1H), 7.4-7.33 (m, 5H), 5.07 (s, 1H), 4.82 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.46 (m, 2H), 3.2-3.15 (m, 2H).
  • ES ⁇ MS calcd. for C 11 H 14 N 2 O 2 S (238.08). Found: 239.1 [M+H].
  • 1H NMR (DMSO-d6) 11.32 (bs, 1H), 7.51-7.36 (m, 9H), 7.23-7.19 (m, 1H), 7.09-6.99 (m, 4H), 5.41 (bs, 1H), 4.76 (s, 2H), 3.95-3.87 (m, 2H), 3.19-3.10 (m, 2H).
  • ES ⁇ MS calcd. for C 24 H 22 N 2 O 4 S (434.13). Found: 435.1 [M+H].
  • 1H NMR (DMSO-d6) 11.23 (bs, 1H), 7.58 (bs, 1H), 7.47-7.41 (m, 4H), 7.24-7.19 (m, 1H), 7.12-7.03 (m, 4H), 5.3 (bs, 1H), 4.05 (bs, 2H), 3.77-3.68 (m, 1H), 3.51-3.41 (m, 1H).
  • ES ⁇ MS calcd. for C 17 H 16 N 2 O 6 S (376.39). Found: 375.2 [M ⁇ H].
  • 1H NMR (DMSO-d6) 5.29-5.22 (bs, 1H), 4.52 (bs, 2H), 3.64-3.52 (m, 2H), 1.55 (bs, 9H).
  • ES ⁇ MS calcd. for C 9 H 15 NO 4 S (233.07). Found: 256.2 [M+Na].
  • 1H NMR (DMSO-d6) 11.474 (bs, 1H), 7.6-7.55 (m, 5H), 4.97 (bs, 1H), 3.94-3.8 (m, 2H), 3.44-3.23 (m, 2H), 1.58-1.53 (m, 9H).
  • ES ⁇ MS calcd. for C 16 H 22 N 2 O 4 S (338.13). Found: 337.2 [M ⁇ H].
  • Step 3 (S)—N-(Benzyloxy)thiazolidine-2-carboxamide hydrochloride salt was prepared from (S)-tert-butyl 2-(benzyloxycarbamoyl)thiazolidine-3-carboxylate following Method F (quantitative yield) 1H NMR (DMSO-d6): 11.91 (bs, 1H), 7.4-7.33 (m, 5H), 5.07 (s, 1H), 4.82 (m, 2H), 3.67-3.56 (m 2H), 3.55-3.46 (m, 2H), 3.2-3.15 (m, 2H).
  • ES ⁇ MS calcd. for C 11 H 14 N 2 O 2 S (238.08). Found: 239.1 [M+].
  • 1H NMR (DMSO-d6) 5.29-5.22 (bs, 1H), 4.52 (bs, 2H), 3.64-3.52 (m, 2H), 1.55 (bs, 9H).
  • ES ⁇ MS calcd. for C 9 H 15 NO 4 S (233.07). Found: 256.2 [M+Na].
  • 1H NMR (DMSO-d6) 11.474 (bs, 1H), 7.6-7.55 (m, 5H), 4.97 (bs, 1H), 3.94-3.8 (m, 2H), 3.44-3.23 (m, 2H), 1.58-1.53 (m, 9H).
  • ES ⁇ MS calcd. for C 16 H 22 N 2 O 4 S (338.13). Found: 337.2 [M ⁇ H].
  • Step 3 (S)—N-(Benzyloxy)thiazolidine-2-carboxamide hydrochloride salt was prepared from (S)-tert-butyl 2-(benzyloxycarbamoyl)thiazolidine-3-carboxylate following Method F (quantitative yield) 1H NMR (DMSO-d6): 11.91 (bs, 1H), 7.4-7.33 (m, 5H), 5.07 (s, 1H), 4.82 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.46 (m, 2H), 3.2-3.15 (m, 2H).
  • ES ⁇ MS calcd. for C 11 H 14 N 2 O 2 S (238.08). Found: 239.1 [M+H].
  • ES ⁇ MS calcd. for C 24 H 21 FN 2 O 3 S (436.13). Found: 435 [M ⁇ H].
  • HPLC: Rt 6.086 min following Method R.
  • ES ⁇ MS calcd. for C 24 H 21 FN 2 O 3 S (468.12). Found: 469 [M+H].
  • 1H NMR (DMSO-d6) 5.29-5.22 (bs, 1H), 4.52 (bs, 2H), 3.64-3.52 (m, 2H), 1.55 (bs, 9H).
  • ES ⁇ MS calcd. for C 9 H 15 NO 4 S (233.07). Found: 256.2 [M+Na].
  • 1H NMR (DMSO-d6) 11.474 (bs, 1H), 7.6-7.55 (m, 5H), 4.97 (bs, 1H), 3.94-3.8 (m, 2H), 3.44-3.23 (m, 2H), 1.58-1.53 (m, 9H).
  • ES ⁇ MS calcd. for C 16 H 22 N 2 O 4 S (338.13). Found: 337.2 [M ⁇ H].
  • Step 3 (S)—N-(Benzyloxy)thiazolidine-2-carboxamide hydrochloride salt was prepared from (S)-tert-butyl 2-(benzyloxycarbamoyl)thiazolidine-3-carboxylate following Method F (quantitative yield) 1H NMR (DMSO-d6): 11.91 (bs, 1H), 7.4-7.33 (m, 5H), 5.07 (s, 1H), 4.82 (m, 2H), 3.67-3.56 (m, 2H), 3.55-3.46 (m, 2H), 3.2-3.15 (m, 2H).
  • ES ⁇ MS calcd. for C 11 H 14 N 2 O 2 S (238.08). Found: 239.1 [M+H].
  • Step 1 Protection (Boc 2 O, base); Step 2: Methyl ester formation (TMSCHN 2 , MeOH); Step 3: Inversion (Ph 3 P, DIAD, Benzoic acid, THF); Step 4: De-O-benzylation (NaOMe, MeOH); Step 5: Deprotection (4M HCl/Dioxane); Step 6: Coupling (ArCOOH, HATU, DIEA, DMF); Step 7: Amidation (Me 3 Al, NH 2 —OBn.HCl, Toluene); Step 8: Hydroxamate formation (10% Pd(OH) 2 /C, EtOH).
  • 1H NMR (DMSO-d6) 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.1 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H).
  • ES ⁇ MS calcd. for C 10 H 17 NO 5 (231.25). Found: 230.2 [M ⁇ H].
  • test compounds and control antibiotics were prepared at 10 mg/ml in DMSO. Serial 2-fold dilutions of each drug were performed in a microtiter plate across each row using DMSO as solvent at 100-fold the desired final concentration. Wells in columns #1-11 contain drug and column #12 was kept as a growth control for the organism with no drug. Each well in the mother plate was diluted with sterile deionized water and DMSO, mixed, and volumes of 10 ⁇ l distributed to each well in the resulting assay plates.
  • Isolated colonies were selected from an 18-24 hr agar plate and resuspended in 0.9% sterile saline to match a 0.5 McFarland turbidity standard using a calorimeter (Vitek) at 80% of transmitance. The suspension was used within 15 minutes of preparation.
  • MLB Mueller-Hinton Broth
  • microtiter plates were incubated 20 h at 35° C. in ambient air.
  • Optical density of each well was determined at 600 nm using a VersaMax Microplate reader (Molecular Devices, Sunnyvale, Calif.). The MIC was defined as the lowest drug concentration causing complete suppression of visible bacterial growth.
  • the compound was dissolved in 10% DMSO, 0.1% Tween 80, 0.9% NaCl solution and administered intravenously at 10 ml/kg at 1 hour after bacterial inoculation.
  • the compound was administered at 80, 40, 20, 5, 2.5, and 1.25 mg/kg.
  • a control with ampicillin was included in the evaluation.
  • mice Male or female ICR mice weighing 22 ⁇ 2 g from MDS Pharma Services were used for the evaluation. Food and water was given ad libitum. Groups of 6 mice weighing 22 ⁇ g were used for the experiment. Mice were inoculated intraperitoneally with Escherichia coli ATCC 25922 at 4 ⁇ 10 4 CFU in 0.5 ml of Brain Heart Infusion Broth (Difco) containing 5% mucin (Sigma). Mortality was recorded once daily for 7 days following bacterial inoculation. The ED50 was determined by non-linear regression and is 28.3 for the compound and 14.1 for ampicillin.
  • test compounds and control antibiotics are prepared at 10 mg/ml in DMSO and are diluted in the assay buffer to 6-fold the final testing concentration. 5 ⁇ l compound dilution is distributed to the well of the assay plate. EDTA is used as positive control and the final concentration in assay is 12.5 mM.
  • P. ae LpxC enzyme dilution in the assay buffer is added to the compound in plate and pre-incubated with the compound at room temperature for 10 min.
  • LpxC substrate is added to initiate the enzyme reaction and the final enzyme and substrate concentrations are 1.2 ⁇ M and 0.4 mM, respectively.
  • the reaction continues at RT for 4 hrs before diluted with 45 ⁇ l of Borate buffer (0.4 M, pH9), followed by addition of 40 ⁇ l derivatization reagent (fluorescamine 2 mg/ml DMF). This mixture is incubated at RT for 10 min followed by addition of 150 ⁇ l DMF/H 2 O (1:1).
  • the resulting solution is loaded onto Millipore filter unit (Microcon 10 k MWCO) and spun at 13 k rpm on bench top centrifuge for 15 min. 100 ⁇ l of this filtrate is transferred to a low fluorescence clear-bottom 96-well plate (Corning) and the fluorescence is detected at ex360 nm and em465 nm on a Tecan fluorescence plate reader. The percent inhibition is calculated based on EDTA produces 100% inhibition and negative control produces 100% activity.
  • Millipore filter unit Microcon 10 k MWCO
  • the range C 1 -C 6 includes the subranges C 2 -C 6 , C 3 -C 6 , C 3 -C 5 , C 4 -C 6 , etc., as well as C 1 (methl), C 2 (ethyl), C 3 (propyl), C 4 (butyl), C 5 (pentyl) and C 6 (hexyl) individually.
  • all language such as “up to,” “at least,” “greater than,” “less than,” “more than,” “or more” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.
  • all ratios disclosed herein also include all subratios falling within the broader ratio.
  • the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the present invention encompasses not only the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyrrole Compounds (AREA)
US12/097,307 2005-12-15 2006-12-04 N-hydroxyamide derivatives possessing antibacterial activity Expired - Fee Related US8088804B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/097,307 US8088804B2 (en) 2005-12-15 2006-12-04 N-hydroxyamide derivatives possessing antibacterial activity

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US75060005P 2005-12-15 2005-12-15
PCT/IB2006/003549 WO2007069020A2 (fr) 2005-12-15 2006-12-04 Derives de n-hydroxyamide possedant une activite antibacterienne
US12/097,307 US8088804B2 (en) 2005-12-15 2006-12-04 N-hydroxyamide derivatives possessing antibacterial activity

Publications (2)

Publication Number Publication Date
US20100022605A1 US20100022605A1 (en) 2010-01-28
US8088804B2 true US8088804B2 (en) 2012-01-03

Family

ID=38163279

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/097,307 Expired - Fee Related US8088804B2 (en) 2005-12-15 2006-12-04 N-hydroxyamide derivatives possessing antibacterial activity

Country Status (5)

Country Link
US (1) US8088804B2 (fr)
EP (2) EP1963262A2 (fr)
JP (1) JP2009520695A (fr)
CA (1) CA2634005C (fr)
WO (1) WO2007069020A2 (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1539744A4 (fr) 2002-07-11 2007-06-06 Vicuron Pharm Inc Derives de n-hydroxyamide ayant une activite anti-bacterienne
WO2008154642A2 (fr) 2007-06-12 2008-12-18 Achaogen, Inc. Agents antibactériens
US20110015158A1 (en) 2007-12-11 2011-01-20 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
AU2009276343A1 (en) * 2008-08-01 2010-02-04 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same
EP2334636A2 (fr) 2008-09-19 2011-06-22 Pfizer Inc. Dérivés d'acide hydroxamique utiles comme agents antibactériens
RU2503443C2 (ru) * 2008-11-19 2014-01-10 Пола Кемикал Индастриз Инк. Средства против морщин
CA2774250C (fr) * 2009-10-13 2013-12-17 Pfizer Inc. Derives d'acide hydroxamique a liaison c utiles comme agents antibacteriens
PL2512474T3 (pl) 2009-12-16 2015-03-31 Pfizer N-przyłączone pochodne kwasu hydroksamowego użyteczne jako środki przeciwbakteryjne
PH12012502087A1 (en) 2010-04-20 2015-04-15 Taisho Pharmaceutical Co Ltd Novel hydroxamic acid derivative
AP3336A (en) * 2011-03-07 2015-07-31 Pfizer Fluoro-pyridinone derivatives useful as antibacterial agents
CN103717582B (zh) 2011-04-08 2015-09-30 辉瑞大药厂 用作抗菌剂的异*唑衍生物
SG193458A1 (en) * 2011-04-08 2013-10-30 Pfizer Imidazole, pyrazole, and triazole derivatives useful as antibacterial agents
JP6006609B2 (ja) * 2011-10-19 2016-10-12 大正製薬株式会社 新規なヒドロキサム酸誘導体を含有する医薬
WO2013170165A1 (fr) 2012-05-10 2013-11-14 Achaogen, Inc. Agents antibactériens
TR201911245T4 (tr) 2013-03-15 2019-08-21 Fujifilm Toyama Chemical Co Ltd Yeni hidroksamik asit türevi veya bunun tuzu.
EP2883876A1 (fr) 2013-12-16 2015-06-17 Actelion Pharmaceuticals Ltd. Synthèse stéréoselective de pyrrolidines substituées
KR20170048546A (ko) 2014-09-12 2017-05-08 토야마 케미칼 컴퍼니 리미티드 신규 히드록삼산 유도체 또는 그 염을 함유하는 의약 조성물
JPWO2016039432A1 (ja) 2014-09-12 2017-06-22 富山化学工業株式会社 新規なヒドロキサム酸誘導体および抗菌性物質を組み合わせて使用する方法
CN108569991A (zh) * 2018-05-31 2018-09-25 常州制药厂有限公司 一种抗丙肝病毒药物关键中间体的制备方法

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4077998A (en) 1975-10-28 1978-03-07 Morton-Norwich Products, Inc. Phthaloyl amino acid hydroxamic acids
WO1997005105A1 (fr) 1995-07-26 1997-02-13 Pfizer Inc. Derives d'acide hydroxamique n-(aroyl)glycine et composes apparentes
WO1997017070A1 (fr) 1995-11-06 1997-05-15 University Of Pittsburgh Inhibiteurs de proteine-isoprenyle-transferases
US6218389B1 (en) 1997-07-31 2001-04-17 The Procter & Gamble Co. Acyclic metalloprotease inhibitors
WO2004007444A2 (fr) 2002-07-11 2004-01-22 Vicuron Pharmaceuticals, Inc. Derives de n-hydroxyamide ayant une activite anti-bacterienne
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
WO2004062601A2 (fr) 2003-01-08 2004-07-29 Chiron Corporation Agents antibacteriens
WO2005037257A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres
WO2006013209A2 (fr) 2004-08-02 2006-02-09 Genmedica Therapeutics Sl Composes inhibant les amine oxydases contenant du cuivre, et utilisations correspondantes
WO2006040646A1 (fr) 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
WO2007017728A2 (fr) 2005-08-05 2007-02-15 Orchid Research Laboratories Limited Nouveaux composes heterocycliques
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925659A (en) 1996-05-07 1999-07-20 Merck & Co., Inc. Antibacterial agents
US6784173B2 (en) * 2001-06-15 2004-08-31 Hoffmann-La Roche Inc. Aromatic dicarboxylic acid derivatives

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4077998A (en) 1975-10-28 1978-03-07 Morton-Norwich Products, Inc. Phthaloyl amino acid hydroxamic acids
WO1997005105A1 (fr) 1995-07-26 1997-02-13 Pfizer Inc. Derives d'acide hydroxamique n-(aroyl)glycine et composes apparentes
WO1997017070A1 (fr) 1995-11-06 1997-05-15 University Of Pittsburgh Inhibiteurs de proteine-isoprenyle-transferases
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6218389B1 (en) 1997-07-31 2001-04-17 The Procter & Gamble Co. Acyclic metalloprotease inhibitors
WO2004007444A2 (fr) 2002-07-11 2004-01-22 Vicuron Pharmaceuticals, Inc. Derives de n-hydroxyamide ayant une activite anti-bacterienne
WO2004062601A2 (fr) 2003-01-08 2004-07-29 Chiron Corporation Agents antibacteriens
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
WO2005037257A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres
WO2006013209A2 (fr) 2004-08-02 2006-02-09 Genmedica Therapeutics Sl Composes inhibant les amine oxydases contenant du cuivre, et utilisations correspondantes
US20080269282A1 (en) * 2004-08-02 2008-10-30 Genmedica Therapeutics Sl Compounds for Inhibiting Copper-Containing Amine Oxidases and Uses Thereof
WO2006040646A1 (fr) 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
WO2007017728A2 (fr) 2005-08-05 2007-02-15 Orchid Research Laboratories Limited Nouveaux composes heterocycliques
US20100152188A1 (en) 2005-08-05 2010-06-17 Akella Satya Surya Visweswara Srinivas Novel Heterocyclic Compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Burdick, D J et al., "N-Benzoyl Amino Acids as LFA-1/ICAM Inhibitors 1: Amino Acid Structure-Activity Relationship", Bioorganic & Medicinal Chemistry Letters, 2003, pp. 1015-1018, vol. 13, No. 6, Oxford, GB.
Grant et al., Bioorganic Chemistry, vol. 29, pp. 211-222 (2001).
Grant, Stephan K, et al., "Inhibition and Structure/Activity Studies of Methionine Hydroxamic Acid Derivatives with Bacterial Peptide Deformylase", Bioorganic Chemistry, 2001, pp. 211-222, vol. 29.

Also Published As

Publication number Publication date
EP2338878A3 (fr) 2011-11-16
CA2634005C (fr) 2012-01-03
EP2338878A2 (fr) 2011-06-29
WO2007069020A3 (fr) 2008-06-19
JP2009520695A (ja) 2009-05-28
US20100022605A1 (en) 2010-01-28
WO2007069020A2 (fr) 2007-06-21
CA2634005A1 (fr) 2007-06-21
EP1963262A2 (fr) 2008-09-03

Similar Documents

Publication Publication Date Title
US8088804B2 (en) N-hydroxyamide derivatives possessing antibacterial activity
US7166590B2 (en) Amino acid derivatives
KR100848491B1 (ko) 베타아미노기를 갖는 2-싸이아졸리딘 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법
EP0445206B1 (fr) Inhibiteurs de collagenase a base d'acide hydroxamique
JP3909056B2 (ja) ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
JP3827324B2 (ja) 金属タンパク質分解酵素阻害剤
US20090149509A1 (en) Novel pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
CA2263932A1 (fr) Inhibiteurs 1,4-heterocycliques de metalloproteases
JP2003528079A (ja) 複素環式側鎖含有メタロプロテアーゼ阻害剤
KR20010042535A (ko) 파파인 상과의 시스테인 프로테아제 저해에 의한 기생충질환의 치료
SK15242003A3 (sk) N-Formylhydroxylamínové zlúčeniny, spôsob ich prípravy a farmaceutické prostriedky s ich obsahom
JP2005504078A (ja) カテプシン阻害剤としての新規化合物および組成物
WO2002098850A2 (fr) Nouveaux composes et compositions utilises en tant qu'inhibiteurs de cathepsine
AU2002305790A1 (en) Chemical compounds and pharmaceutical compositions as cathepsin S inhibitors
AU776171B2 (en) Alpha-amino-beta-sulfonyl hydroxamic acid compounds
US7427634B2 (en) Amino acid derivatives and pharmaceutical composition comprising, as active ingredients, them
US20070259965A1 (en) Acyclic 1,3-Diamine And Uses Therefor
KR20020038951A (ko) 베타 이치환된 메탈로프로테아제 저해제
WO1998023588A9 (fr) Inhibiteurs de metalloproteinases
US11208421B2 (en) 2-carboxypenam compound or salt thereof, pharmaceutical composition containing novel 2-carboxypenam compound or salt thereof, and applications thereof
RU2768755C1 (ru) Новое соединение, проявляющее ингибирующую активность в отношении энтеропептидазы
KR20040095339A (ko) 히드록시모르폴리논 유도체 및 이의 의약 용도

Legal Events

Date Code Title Description
AS Assignment

Owner name: VICURON PHARMAECUTICALS INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JAIN, RAKESH KUMAR;GORDEEV, MIKHAIL FEDOROVICH;LEWIS, JASON GUSTAF;AND OTHERS;REEL/FRAME:021990/0912;SIGNING DATES FROM 20081106 TO 20081119

Owner name: VICURON PHARMAECUTICALS INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JAIN, RAKESH KUMAR;GORDEEV, MIKHAIL FEDOROVICH;LEWIS, JASON GUSTAF;AND OTHERS;SIGNING DATES FROM 20081106 TO 20081119;REEL/FRAME:021990/0912

AS Assignment

Owner name: VICURON HOLDINGS LLC, NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VICURON PHARMACEUTICALS INC.;REEL/FRAME:023720/0776

Effective date: 20091202

Owner name: VICURON HOLDINGS LLC,NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VICURON PHARMACEUTICALS INC.;REEL/FRAME:023720/0776

Effective date: 20091202

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20160103